Genetic Relationship Between Five Psychiatric Disorders Estimated From Genome-Wide SNPs

a n a ly s i s
Genetic relationship between five psychiatric disorders

estimated from genome-wide SNPs
npg
2013 Nature America, Inc. All rights reserved.
Cross-Disorder Group of the Psychiatric Genomics Consortium*

Most psychiatric disorders are moderately to highly heritable.
The degree to which genetic variation is unique to individual
disorders or shared across disorders is unclear. To examine
shared genetic etiology, we use genome-wide genotype data
from the Psychiatric Genomics Consortium (PGC) for cases
and controls in schizophrenia, bipolar disorder, major
depressive disorder, autism spectrum disorders (ASD) and
attention-deficit/hyperactivity disorder (ADHD). We apply
univariate and bivariate methods for the estimation of
genetic variation within and covariation between disorders.
SNPs explained 1729% of the variance in liability.
The genetic correlation calculated using common SNPs
was high between schizophrenia and bipolar disorder
(0.68 0.04 s.e.), moderate between schizophrenia and major
depressive disorder (0.43 0.06 s.e.), bipolar disorder and
major depressive disorder (0.47 0.06 s.e.), and ADHD and
major depressive disorder (0.32 0.07 s.e.), low between
schizophrenia and ASD (0.16 0.06 s.e.) and non-significant
for other pairs of disorders as well as between psychiatric
disorders and the negative control of Crohns disease. This
empirical evidence of shared genetic etiology
for psychiatric disorders can inform nosology and encourages
the investigation of common pathophysiologies for
related disorders.
The current classification of psychiatric disorders reflects clinical
syndromes with largely unknown etiology and is based on historical
descriptions provided by prominent clinicians over the last 125 years.
Family (including twin and adoption) studies provide consistent evidence that genetic factors are involved in these syndromes1. In principle, family studies allow quantification of the shared genetic etiology
of disorders, through the estimation of heritability (the proportion of
variance in liability attributable to additive genetic factors), and the
genetic correlation between them. However, difficulties in ascertaining
samples of sufficient size mean that there are few estimates of genetic
correlations. Nonetheless, family studies suggest correlated familial
genetic liabilities to bipolar disorder and schizophrenia2,3, bipolar
disorder and major depressive disorder2,3, and ASD and ADHD46
(Supplementary Table 1). Phenotypic and genetic overlap has also
*A
full list of authors and affiliations appears at the end of the article.
Received 10 February; accepted 28 June; published online 11 August 2013;

doi:10.1038/ng.2711
984
been suggested for ASD and schizophrenia711, ASD and bipolar disorder9, bipolar disorder and ADHD12, and major depressive disorder
and ADHD13. Some of these relationships have been supported by
recent evidence of shared molecular risk factors1416, but the extent
of these relationships remains unclear, given the small proportion of
risk associated with individually identified variants.
The genomics era provides new opportunities to explore the shared
genetic etiology of disorders. Genome-wide association studies
(GWAS) assess common genetic polymorphisms (for example, SNPs)
at several hundred thousand positions in the genome. The experimental paradigm of GWAS involves the identification of individual
variants associated with case-control status17. However, these data
can also be used to estimate the total variance in liability explained
2
by SNPs (SNP heritability, hSNP
) through the estimation of genetic
similarities (relationships) between cases and controls using SNP
genotypes18,19. The pairwise genetic relationships that contribute to
the estimate are very small, but the large number of pairwise relationships in a case-control sample generates estimates with reason2
able precision. The hSNP
value is an estimate of the total variance
in liability to disease explained by SNPs together. Genetic variation
is estimated when case-case pairs and control-control pairs are, on
average, more similar across the genome than case-control pairs. The
2
hSNP
value is a lower bound for total narrow-sense heritability, as the
former cannot include contributions from causal variants not tagged
by the measured SNPs, mostly less common and rare causal variants.
A bivariate extension20 of these genome-wide methods estimates
the genetic correlation (rg SNP) explained by SNPs between casecontrol samples collected independently for two disorders (Online
Methods). The correlation is positive when the cases of one disorder
show higher genetic similarity to the cases of the other disorder
than they do to their own controls. A negative correlation is possible if the cases of one disorder are less similar across the genome
to the cases of another disorder than they are to controls of the other
disorder. A genetic correlation of zero is estimated if the genomewide relationship between cases of one disorder is the same with
the cases as with the controls of another disorder. As a correlation,
a high rg SNP value is achieved when the covariance term between
the traits is similar in magnitude to the variance terms. Therefore,
we also report the SNP-based coheritability of pairs of disorders,
which is the covariance between disorders on the liability scale and
allows comparison of the shared liability attributable to SNPs on the
2
same scale as hSNP
. Here we apply univariate and bivariate methods
to the five disorders of the PGCschizophrenia21, bipolar disorder22,
major depressive disorder23, ASD24,25 and ADHD26analyzed in the
VOLUME 45 | NUMBER 9 | SEPTEMBER 2013 Nature Genetics
a n a ly s i s
npg
PGC Cross-Disorder Group association study25, together with additional ADHD data sets2730 (Table 1).
RESULTS
SNP heritabilities for the five disorders
In our linear mixed model, we estimate the variance in case-control
status explained by SNPs18 (heritability on the observed scale; CC
estimates in Table 1). Cases in case-control samples are highly ascertained compared to in the population, and, because the cohorts for
different disorders had different proportions of cases, CC estimates
were difficult to interpret and compare. For this reason, we report
2
values on the liability scale, in which a linear transformation18 is
hSNP
applied based on a user-specified estimate of the risk of the disorder
in the study base population (disorder risk, K). For each disorder,
2
we considered three values of K (Table 1), and we converted hSNP
values to predicted risk to first-degree relatives (1st SNP) given K. We
benchmarked the 1st SNP risk values to risk to first-degree relatives
(1st), consistent with estimates of heritability reported from family
studies given K. Our estimates of 1st SNP values were robust, and our
2
estimates of hSNP
values were reasonably robust, to the likely range
of K values and show that a key part of the heritabilities or familial
risk estimated from family studies is associated with common SNPs.
Twice the standard error of estimates approximates the magnitude of
the parameter that is possible to detect as being significantly different
from zero, given the available sample sizes31.
SNP coheritabilities and SNP correlations (rg SNP)
The relationships between disorders were expressed as SNPbased coheritabilities (Fig. 1). The rg SNP value was high between
schizophrenia and bipolar disorder at 0.68 (0.04 standard error (s.e.)),
moderate between schizophrenia and major depressive disorder at

0.43 (0.06 s.e.), bipolar disorder and major depressive disorder at
0.47 (0.06 s.e.), and ADHD and major depressive disorder at 0.32
(0.07 s.e.), low between schizophrenia and ASD at 0.16 (0.06 s.e.)
and non-significant for other pairs of disorders (Supplementary
Table 1). The rg SNP value for correlation is expected to be equal to
the rg value from family studies only if genetic correlation is the same
across the allelic frequency spectrum and if the linkage disequilibrium (LD) between genotyped and causal variants is similar for both
disorders. The sample size for ASD was the smallest but still could
detect correlations of >|0.18| different from zero in bivariate analyses
with all other disorders.
Our results provide empirical evidence that schizophrenia, bipolar
disorder and major depressive disorder have shared genetic etiology.
Because some schizophrenia and bipolar disorder cohorts were collected in the same clinical environments, we investigated the possible impact of the non-independent collection of schizophrenia and
bipolar disorder samples sets but found no significant change in the
estimates related to this (Supplementary Table 2). The correlation
between schizophrenia and ASD was significant but small (0.16, 0.06
s.e.; P = 0.0071). In general, our analyses suggested that, whereas common genetic variants contribute to both childhood-onset disorders
(ASD and ADHD) and disorders usually diagnosed after childhood
(schizophrenia, bipolar disorder and major depressive disorder), the
sharing of common variants between these groups is modest.
The pattern of our results (in which pairs of disorders demonstrated
genetic overlap) was consistent with polygenic profile score32 results
from PGC cross-disorder analyses25. The profile score method uses
SNP associations from one disorder to construct a linear predictor in
another disorder. The profile scores explained small but significant
Table 1 Univariate analyses: sample description, SNP-based heritabilities and recurrence risk to first-degree relatives
Schizophrenia
SNPs (imputed)
Cases
Controls
915,354
9,087
12,171
Bipolar disorder
995,971
6,704
9,031
Major depressive disorder

962,093
9,041
9,381
ASD
982,100
3,303
3,428a
ADHD
917,066
4,163
12,040a
N cohorts
Primary reference
CC (s.e.)
17
21
0.41 (0.015)
11
22
0.44 (0.021)
9
23
0.18 (0.017)
8
24,25
0.31 (0.046)
8
2630
0.25 (0.020)
Disorder risk for the study-based population (disorder risk, K)b

K
2
(s.e.)
hSNP
1st-SNP (s.e)
1st
0.01
0.23 (0.008)
2.10 (0.05)
8.8
0.01
0.25 (0.012)
2.23 (0.08)
9.6
0.15
0.21 (0.021)
1.27 (0.03)
1.5
0.01
0.17 (0.025)
1.75 (0.14)
8.7
0.05
0.28 (0.023)
1.71 (0.07)
3.5
Lower bound for disorder risk (K)

K
2
hSNP
(s.e.)
0.004
0.007
0.1
0.001
0.03
1st-SNP (s.e)
1st
Upper bound for disorder risk (K)

K
2
hSNP
(s.e.)
1st-SNP (s.e)
1st
0.19 (0.007)
2.14 (0.06)
14.4
0.23 (0.010)
2.25 (0.08)
11.7
0.19 (0.018)
1.31 (0.03)
1.7
0.11 (0.017)
1.79 (0.15)
29.4
0.24 (0.020)
1.77 (0.07)
4.5
0.012
0.015
0.2
0.015
0.08
0.24 (0.009)
2.10 (0.05)
8.0
0.27 (0.013)
2.20 (0.07)
7.7
0.23 (0.023)
1.24 (0.02)
1.4
0.19 (0.028)
1.74 (0.13)
7.0
0.32 (0.026)
1.65 (0.06)
2.8
0.75
0.37
0.80
0.75
Heritability estimated from twin/family studies61

h2
0.81
CC is the SNP-based heritability estimated on case-control scale. h2SNP is the SNP-based heritability on liability scale, given assumed K. All estimates of h2SNP are highly
significantly different from zero. 1st-SNP is the recurrence risk to first-degree relatives calculated from h2SNP and K. 1st is the recurrence risk to first-degree relatives calculated
from h2 from twin and/or family studies and K.
aSome
cohorts include cases and pseudocontrols, where pseudocontrols are the genomic complements of the cases derived from genotyping of proband-parent trios. bUsed in Figures 1 and 3
Supplementary Tables 18.
Nature Genetics VOLUME 45 | NUMBER 9 | SEPTEMBER 2013
985
a n a ly s i s
Genomic partitioning of SNP heritabilities and coheritabilities

The heritabilities explained by SNPs can be partitioned according to
SNP annotation by the estimation of genetic similarity matrices from
multiple, non-overlapping SNP sets. For the five disorders and the five
disorder pairs showing significant SNP correlation, we partitioned
2
the hSNP
and SNP-based coheritabilities explained by functional
annotation, allocating SNPs to one of three sets: (i) SNPs in genes
preferentially expressed in the central nervous system (CNS+) 34,35,
(ii) SNPs in other genes and (iii) SNPs not in genes, with genes defined
by 50-kb boundaries extending from their start and stop positions.
The SNPs in the CNS+ gene set represented 0.20 of the total set,
both in number and megabases of DNA. However, the proportion
of the variance explained by SNPs attributable to this SNP set was
significantly greater than 0.20 for schizophrenia (0.30; P = 7.6 108)
and bipolar disorder (0.32; P = 5.4 106) and for schizophrenia
and bipolar disorder coheritability (0.37; P = 8.5 108) (Fig. 2 and
Supplementary Table 3). For other disorders or pairs of disorders,
the estimates explained by CNS+ SNPs did not differ from the values
expected by chance (Supplementary Table 3), although their large
standard errors suggest that we cannot address this question with
precision. For data from the schizophrenia and bipolar disorder pair,
we also partitioned the heritabilities explained by SNPs by minor
allele frequency (MAF) (Supplementary Table 4) and by chromosome (Supplementary Fig. 1). The high standard errors on estimates
limited interpretation, but the results are consistent with a polygenic
architecture comprising many common variants of small effect dispersed throughout the genome. The MAF partitioning suggests that a
key part of the variance explained by SNPs is attributable to common
causal variants (this was investigated in detail for schizophrenia35),
986
0.7
0.6
0.5
***
0.4
***
0.3
***
0.2
0.1
0
Crohns disease
proportions of the variance25, expressed as Nagelkerkes R2 (maximum

of 2.5% between schizophrenia and bipolar disorder). To achieve high
R2 values requires accurate estimation of the effect sizes of individual
SNPs and depends on the size of the discovery sample. In contrast,
our approach uses SNPs to estimate genome-wide similarities between
pairs of individuals, resulting in unbiased estimates of the relationships between disorders, with larger sample sizes generating smaller
standard errors for the estimates. Our estimates were on the liability
scale, allowing direct comparison to genetic parameters estimated in
family studies, whereas a genetic interpretation of Nagelkerkes R2
values is less straightforward33.
ADHD
npg
Figure 1 Evidence for genome-wide pleiotropy between psychiatric

disorders. Proportion of variance in liability (SNP-based heritability)
and proportion of covariance in liability between disorder (SNP-based
coheritability) for five major psychiatric disorders. The 95% error bars
represent the estimates 1.96 s.e. SCZ, schizophrenia; MDD, major
depressive disorder; BPD, bipolar disorder.
SCZ-MDD
ADHD
BPD
SCZ
MDD
ASD
SCZ-BPD
BPD-MDD
SCZ-MDD
MDD-ADHD
SCZ-ASD
SCZ-ADHD
BPD-ADHD
MDD-ASD
BPD-ASD
ASD-ADHD
0.10
MDD
0
0.05
Within-disorder heterogeneity
To benchmark the estimates of genetic sharing across disorders, we
estimated sharing between data subsets for the same disorder. We
split the data for each disorder into two or three independent sets
2
and estimated hSNP
values for each subset and the SNP-based coheritability between each pair of subsets within a disorder (Fig. 3a and
2
Supplementary Table 5). The estimates of hSNP
from the data sub2
sets were typically higher than the hSNP estimate from the combined
sample; we note that published estimates from individual cohorts
of bipolar disorder18, major depressive disorder36 and ASD37 were
also higher. Because both traits in these data subset bivariate analyses
are for the same disorder, the SNP-based coheritability is also an
2
estimate of hSNP
for the disorder, but these estimates were generally lower than the estimates of SNP-based heritability from individual data subsets. These results generated SNP-based correlations
that were less than 1, sometimes significantly so (Supplementary
Table 5). The SNP-based correlation between schizophrenia and
bipolar disorder (0.68, 0.04 s.e.) was of comparable magnitude to the
SNP-based correlations between bipolar disorder data sets (0.63, 0.11
s.e.; 0.88, 0.09 s.e.; and 0.55, 0.10 s.e.; Fig. 3a,b, SNP-based coheritabilities), adding further weight to the conclusion that schizophrenia
and bipolar disorder may be part of the same etiological spectrum.
The estimates of heritability from both univariate (Fig. 3a, red
and pink bars) and bivariate (Fig. 3a, blue bars) analyses are more
heterogeneous for bipolar disorder, major depressive disorder and
ADHD than they are for schizophrenia and ASD. Several factors could
explain why SNP-based heritabilities from univariate analyses of a
single data set could generate higher estimates than bivariate analyses
of independent data sets35, including loss of real signal or dilution of
artifacts. Loss of real signal might occur because individual cohorts
are more homogeneous, both phenotypically (for example, owing to
MDD-ADHD
0.05
BPD-MDD
0.10
SCZ
0.15
SCZ-ASD
0.20
BPD
0.25
but the low contribution to the total variance explained by SNPs with
MAF of <0.1 reflects, at least in part, under-representation of SNPs
with low MAFs in the analysis (minimum MAF = 0.01) relative to
those present in the genome.
ASD
SNP-based heritability
0.30
SNP
Coheritabilities
SCZ-BPD
Heritabilities
Proportion
0.35
Figure 2 Genomic partitioning of SNP-based heritability and SNP-based

coheritability by annotation. Shown is the proportion of SNPs attributable
to genes in the CNS+ set (red), the proportion of SNP-based heritability
attributable to SNPs in the CNS+ set (dark green), the proportion of
SNP-based coheritability attributable to SNPs in the CNS+ set (light
green) and the proportion of SNP-based heritability for Crohns disease
attributed to SNPs in the CNS+ set (orange). The 95% error bars
represent the estimates 1.96 s.e. ***P < 1 105 in a test of whether
the proportion of heritability explained by SNPs was equal to the
proportion of SNP for the CNS+ set.
a n a ly s i s
a
npg
use of the same assessment protocols) and genetically (for example,

because LD between causal variants and analyzed SNPs might be
higher within than between cohorts). Artifacts could also generate
consistent differences in case genotypes relative to control genotypes
within case-control data sets. In the derivation of our methodology18,
we emphasized that any factors making SNP genotypes of cases more
similar to those of other cases and making the genotypes of controls
more similar to those of other controls would produce SNP-based
heritability. The fitting as covariates of principal components derived
from the SNP data corrects both for population stratification and
for genotyping artifacts, but residual population stratification could
remain, although this bias should be small38. Partitioning SNP-based
heritability by chromosome in analyses where each chromosome
was fitted individually compared to analyses where all chromosomes
were fitted jointly is an empirical strategy to assess residual stratification35,39, and we found no evidence of this type of stratification here
(Supplementary Fig. 1). Stringent quality control (as applied here)
helps to remove artifacts, but artifactual differences between cases and
controls might remain, particularly for data sets in which cases and
controls have been genotyped independently40. As more data sets accumulate, the contributions from artifacts are diluted because the random
directional effects of artifacts (including population stratification) are
not consistent across data sets. For this reason, significant SNP-based
coheritabilities between subsets of the same disorder are unlikely to
reflect artifacts and provide a lower bound for SNP-based heritability.
Pseudocontrols
One strategy adopted in GWAS to guard against artifacts from population stratification is to genotype family trio samples (cases and their
parents) and then analyze the data as a case-control sample, with
controls generated as genomic complements of the cases (pseudocontrols). ADHD subset 1 and most of the ASD sample comprised
case-pseudocontrol samples and, consistent with this strategy limiting
the impact of artifacts from population stratification or genotyping,
it is noted that the lowest SNP-based heritability for the five psychiatric disorders was for ASD and that the estimate of SNP-based
heritability was lower for ADHD subset 1 than for ADHD subset 2.
However, under a polygenic model, assortative mating41 or preferential ascertainment of multiplex families could diminish the expected
mean difference in liability between pseudocontrols and cases 37,
which would result in an underestimation of SNP-based heritability from case-pseudocontrol compared to case-control analyses and
Crohns disease
CD-SCZ
CD-BPD
CD-MDD
CD-ASD
CD-ADHD
SCZ-BPD
BPD-MDD
SCZ-MDD
MDD-ADHD
SCZ-ASD
SCZ-ADHD
BPD-ADHD
MDD-ASD
BPD-ASD
ASD-ADHD
SNP-based heritability or coheritability
Figure 3 SNP-based heritabilities and

coheritabilities. (a) For each disorder,
All data
Subset 1
Subset 2
Subset 3
0.7
SNP-based heritabilities are estimated
Subsets 1 and 2
Subsets 1 and 3
Subsets 2 and 3
0.6
Crohns disease analyses
from univariate analyses of the full data
set (dark green) or of sample subsets
0.5
(red and pink bars). These heritabilities
0.4
are also estimated from bivariate analyses in
0.3
which different subsets of the same disorder
comprise the two traits (blue). Test of the
0.2
heterogeneity of estimates, P value for
0.1
Cochrans Q: schizophrenia, 0.3; bipolar
disorder, 1 106; major depressive disorder,
0
4 103; ADHD, 9 106; ASD, 0.99;
SCZ
BPD
MDD
ASD
ADHD
Higgins I2: schizophrenia, 21%; bipolar
disorder, 86%; major depressive disorder,
71%; ADHD, 91%; ASD, 0%). (b) For
comparison, the coheritabilities using the full
data sets reported in Figure 1 are shown.
(c) As a negative control, estimates of coheritabilities with Crohns disease, a disease not expected to be genetically related to psychiatric disorders, are
shown. We estimated 95% error bars using 1.96 s.e.
would also result in nonzero estimates of SNP-based heritability from

pseudocontrol-control analyses, as shown in analysis of ASD data37.
SNP-based coheritabilities with Crohns disease
As a negative control analysis, we conducted bivariate analyses between
each of the PGC data sets and Crohns disease samples from the
International IBD Genetics Consortium (IIBDGC)42. Although onset
of major depressive disorder is not uncommon after diagnosis with
Crohns disease43 and although gastrointestinal pathology is a common comorbidity with ASD44, there is no strong evidence of a familial
relationship between psychiatric disorders and Crohns disease.
2
Despite substantial hSNP values for Crohns disease (0.19, 0.01 s.e.),
none of the SNP-based coheritabilities with the psychiatric disorders
differed significantly from zero (Fig. 3c, Supplementary Table 6
and Supplementary Note). Lastly, genomic partitioning by annotation of the variance in Crohns disease explained by SNPs showed,
as expected, no excess of variance attributable to SNPs in the CNS+
gene set (Fig. 2). Our results provide no evidence of common genetic
pleiotropy in Crohns disease and ASD, consistent with a non-genetic,
for example, microbial45, explanation for the comorbidity of gastrointestinal symptoms in ASD.
Potential impact of misclassification of disorders
Misclassification among disorders could inflate estimates of genetic
correlation and/or coheritability46. Indeed, some level of misclassification in psychiatric disorders is expected. For example, longitudinal studies47,48 of first admissions with psychosis showed that,
with long-term follow-up, ~15% of subjects initially diagnosed with
bipolar disorder were rediagnosed with schizophrenia, whereas ~4%
of schizophrenia diagnoses were reclassified as bipolar disorder.
Cases selected for GWAS contributing to PGC are more likely to
have achieved a stable diagnosis compared to first-admission cases.
However, assuming these levels of misclassification, the genetic correlation between bipolar disorder and schizophrenia for true diagnoses is still high, estimated46 to be 0.55. Likewise, because a modest
proportion of cases diagnosed with major depressive disorder, when
followed over time, ultimately meet criteria for bipolar disorder49,
our estimated genetic correlation between these two disorders may
be modestly inflated by misclassification. However, if moderate-tohigh genetic correlations between the major adult disorders are true,
then overlapping symptoms and misdiagnosis among these disorders
might be expected. The rg SNP value between schizophrenia and major
987
a n a ly s i s
npg
depressive disorder is also unlikely to reflect misdiagnosis because

misclassification between these disorders is rare49. Excluding 5 of
the 18 PGC schizophrenia cohorts containing schizoaffective disorder cases21 (Supplementary Table 7) or major depressive disorder
cohorts ascertained from community rather than clinical settings
(Supplementary Table 8) had little impact on rg SNP estimates.
DISCUSSION
Our results show direct, empirical, quantified molecular evidence
for an important genetic contribution to the five major psychiatric
2
disorders. The hSNP estimates for each disorderschizophrenia, 0.23
(0.01 s.e.), bipolar disorder, 0.25 (0.01 s.e.), major depressive disorder,
0.21 (0.02), ASD, 0.17 (0.02 s.e.) and ADHD, 0.28 (0.02 s.e.)are
considerably less than the heritabilities estimated from family studies
(Table 1). Yet, they show that common SNPs make an important
contribution to the overall variance, implying that additional individual, common SNP associations can be discovered as sample size
2
increases50. hSNP
values are a lower bound for narrow-sense heritability because they exclude contributions from some causal variants
(mostly rare variants) not associated with common SNPs. Although
SNP-based heritability estimates are similar for major depressive disorder and other disorders, much larger sample sizes will be needed, as
high risk for a disorder implies lower power for equal sample size51.
2
The hSNP
values are all lower than those reported for height (0.45, 0.03
39
s.e.) , but the estimates are in the same ballpark as those reported
for other complex traits and diseases using the same quality control pipeline, such as for body mass index (BMI) (0.17, 0.03 s.e.)39,
Alzheimers disease (0.24, 0.03 s.e.), multiple sclerosis (0.30, 0.03 s.e.)
and endometriosis (0.26, 0.04 s.e.)40.
Our results show molecular evidence of the sharing of genetic risk
factors across key psychiatric disorders. Traditionally, quantification
of the genetic relationship between disorders has been thwarted by the
need for cohorts of families or twins assessed for multiple disorders.
Problems of achieving genetically informative samples of sufficient
size and without associated ascertainment biases for the rarer psychiatric disorders have meant that few studies have produced meaningful
estimates of genetic correlations. Notably, our estimates of heritability
and genetic correlation are made using very distant genetic relationships between individuals, both within and between disorders, so
that shared environmental factors are unlikely to contaminate our
estimates. Likewise, our estimates are unlikely to be confounded by
non-additive genetic effects, as the coefficients of non-additive genetic
variance between very distant relatives are negligible52.
The estimates of SNP-based genetic correlation (rg SNP) between
disorders reflect the genome-wide pleiotropy of variants tagged by
common SNPs, and whether these are the same as correlations across
the allelic frequency spectrum may differ between pairs of disorders.
For example, a high rg SNP value but a low genetic correlation estimated
from family studies (rg) could indicate that the same common variants contribute to genetic susceptibility for both disorders, although
the diagnostic-specific variants are less common variants. For this
reason, the comparison of rg SNP with rg estimated from family studies
is not straightforward. Nonetheless, we benchmark our estimates in
this way, calculating the increased risk of disorder B in first-degree
relatives of probands with disorder A (A,B) from the rg SNP value to
allow comparison with literature values (Supplementary Table 1).
A meta-analysis53 reported increased risk of bipolar disorder in firstdegree relatives of probands with schizophrenia compared to firstdegree relatives of control probands (SCZ,BPD) of 2.1, which implies a
maximum genetic correlation between the disorders of 0.3 (assuming
that the disorder risks for schizophrenia and bipolar disorder are both
988
1% and their heritabilities are 81% and 75%, respectively; Table 1).
However, a large-scale Swedish family and adoption study54 estimated
the genetic correlation between schizophrenia and bipolar disorder to
be +0.60, similar to that found here. Profiling scoring analysis using
genome-wide SNPs32 was the first method to clearly demonstrate a
genetic relationship based on molecular data, but quantification as a
genetic correlation was not reported. The evidence of shared genetic
risk factors for schizophrenia and bipolar disorder was strengthened
by our analyses of the CNS+ gene set in which we saw a clear enrichment in variants shared by these two disorders.
Our finding of a substantial rg SNP of +0.43 between schizophrenia and major depressive disorder is notable and contrary to conventional wisdom about the independence of familial risk for these
disorders. However, because major depressive disorder is common,
even a high genetic correlation implies only modest incremental risk.
Assuming the disorder risks and heritabilities for schizophrenia and
major depressive disorder given in Table 1, then the genetic correlation between them of 0.43 predicts increased risk of major depressive disorder in first-degree relatives of probands with schizophrenia
compared to first-degree relatives of control probands (SCZ,MDD) of
1.6. In fact, meta-analysis of five interview-based research studies of
families are broadly consistent with our results (SCZ,MDD = 1.5, 95%
confidence interval (CI) = 1.21.8; Supplementary Table 9), suggesting that familial coaggregation of major depressive disorder and
schizophrenia reflects genetic effects rather than resulting from living
in a family environment that includes a severely ill family member. If
replicated by future work, our empirical molecular genetic evidence of
a partly shared genetic etiology for schizophrenia and major depressive disorder would have key nosological and research implications,
incorporating major depressive disorder as part of a broad psychiatric
genetic spectrum. A shared genetic etiology for bipolar disorder and
major depressive disorder has been shown in family studies2,3, but
the rg SNP value of 0.47 was lower than the estimate of 0.65 from a
twin study55.
Our results show a small but significant rg SNP value between schizophrenia and ASD. A lower genetic correlation between schizophrenia
and ASD than between schizophrenia and bipolar disorder is consistent with Swedish national epidemiological studies, which reported
higher odds ratios in siblings for schizophrenia and bipolar disorder54
than for schizophrenia and ASD9. These results imply a modest overlap of common genetic etiological processes in these two disorders,
consistent with emerging evidence from the discovery of copy number
variants, in which both shared variants (for example, 15q13.3, 1q2.1
and 17q12 deletions56,57) and mutations in the same genes although
with different variants (deletions associated with schizophrenia and
duplications associated with autism and vice-versa10). The small ASD
sample size thwarted attempts at further explorative partitioning of
the SNP-based coheritability for schizophrenia and ASD.
The lack of overlap between ADHD and ASD is unexpected and
is not consistent with family and data linkage studies, which indicate
that the two disorders share genetic risk factors5,6,58,59. Some rare
copy number variants are seen in both disorders16. As noted above,
the use of pseudocontrols for many of the ASD and ADHD cohorts
may affect all results for these disorders. Ideally, we would investigate the impact of pseudocontrols, given the hierarchical diagnostic
system (autism but not autism spectrum is an exclusion criterion for
most ADHD data sets), on estimates of SNP-based coheritability, but
the small ASD sample size prohibits such analyses. We also found no
overlap between ADHD and bipolar disorder, despite support from
meta-analysis results of an increased risk for ADHD in relatives of
individuals with bipolar disorder I (a subtype of bipolar disorder with
npg
a n a ly s i s
more extreme manic symptoms than the other major bipolar disorder subtype) and an increased risk for bipolar disorder I in relatives
of individuals with ADHD12. These findings could mean that the
familial link between the two disorders is mediated by environmental
risk factors or that shared genetic factors are not part of the common
allelic spectrum. Alternatively, the etiological link between ADHD
and bipolar disorder might be limited to bipolar disorder I or earlyonset bipolar disorder12, which, therefore, is difficult for us to detect.
Our finding of genetic overlap between ADHD and major depressive
disorder is consistent with evidence from studies showing increased
rates of ADHD in the families of depressed probands and increased
rates of depression in families of probands with ADHD12,13.
Our results should be interpreted in the context of four potentially
important methodological limitations. First, any artifacts that make
SNP genotypes more similar between cases than between cases and
controls could inflate estimates of SNP-based heritability 18, but to a
much lesser extent for SNP-based coheritability. Second, the sample
2
sizes varied considerably across the five disorders. Although hSNP
values are expected to be unbiased, estimates from smaller samples
are accompanied by larger standard errors, blurring their interpretation. Third, although applying similar diagnostic criteria, the clinical
methods of ascertainment and the specific study protocols, including
which specific interview instruments were employed, varied across
sites. We cannot now determine the degree to which our results
might have been influenced by between-site differences in the kinds
of patients seen or in their assessments. Fourth, by combining samples
from geographic regions, contributions from less common associated variants specific to particular populations are diluted compared
to what would have been achieved if the same sample size had been
ascertained from a single homogeneous population.
In summary, we report SNP-based heritabilities that are significantly greater than zero for all five disorders studied. We have used the
largest psychiatric GWAS data sets currently available, and our results
provide key pointers for future studies. Our results demonstrate that
the dearth of significant associations from psychiatric GWAS so far,
particularly for major depressive disorder, ASD and ADHD, reflects
lack of power to detect common associated variants of small effect
rather than the absence of such variants. Hence, as sample sizes
increase, the success afforded to other complex genetic diseases50 in
increasing the understanding of their etiologies is achievable for psychiatric disorders, as is already being shown for schizophrenia60. We
also provide evidence of substantial sharing of the genetic risk variants
tagged by SNPs between schizophrenia and bipolar disorder, bipolar disorder and major depressive disorder, schizophrenia and major
depressive disorder, ADHD and major depressive disorder, and, to a
lesser extent, between schizophrenia and ASD. Our results will likely
contribute to the efforts now under way to base psychiatric nosology on a firmer empirical footing. Furthermore, they will encourage
investigations into shared pathophysiologies across disorders, including potential clarification of common therapeutic mechanisms.
URLs. PGC, https://pgc.unc.edu/; Genetic Cluster Computer, http://
www.geneticcluster.org/; GCTA, http://www.complextraitgenomics.
com/software/gcta/.
Methods
Methods and any associated references are available in the online
version of the paper.
Note: Any Supplementary Information and Source Data files are available in the
online version of the paper.
Acknowledgments
This research was directly supported by the Australian Research Council
(FT0991360 and DE130100614) and the Australian National Health and Medical
Research Council (613608, 1011506 and 1047956). The PGC Cross-Disorder
Group is supported by National Institute of Mental Health (NIMH) grant
U01 MH085520. Statistical analyses were carried out on the Genetic Cluster
Computer (see URLs), which is financially supported by the Netherlands Scientific
Organization (NOW; 480-05-003; principal investigator D.P.) along with a
supplement from the Dutch Brain Foundation and VU University. Numerous
(>100) grants from government agencies along with substantial private and
foundation support worldwide enabled the collection of phenotype and genotype
data, without which this research would not be possible; grant numbers are listed in
primary PGC publications or in the Supplementary Note.
AUTHOR CONTRIBUTIONS
Project conception: K.S.K., N.R.W. and J.W.S. Analysis: S.H.L. and N.R.W.
Writing of the manuscript: N.R.W., S.H.L., K.S.K. and S.V.F. Quality control
for PGC data: S. Ripke and B.M.N. Revisions to the manuscript: S.M.P., J.W.S.,
R.H.P., B.J.M., P.F.S., A.T., C.O., M.J.D., R.D.O. and J.B. Statistical advice: M.E.G.
and J.S.W. Data access: D.P. PGC Workgroup Chairs: M.J.D. (analysis), S.V.F.
(ADHD), M.J.D. and B.D. (co-chairs ASD), J.K. and P. Sklar (co-chairs bipolar
disorder), P.F.S. (major depressive disorder), M.C.O. (schizophrenia) and J.W.S.
and K.S.K. (co-chairs cross-disorder group). Collection, genotyping and analysis
for PGC Working Groups. PGC ADHD Working Group: B.M.N., S.V.F., A.T.,
R.A., P.A., T. Banaschewski, M. Bays, J.B., J.K.B., M.C., B.C., J.C., A.E.D., R.P.E.,
J.E., B.F., C.M.F., L. Kent, J.K., K.-P.L., S.K.L., J.M., J.J.M., S.E.M., J.M.S., A. Miranda,
S.F.N., R.D.O., J.A.R.-Q., A. Reif, M. Ribass, H.R., A. Rothenberger, J.A.S., R.S.,
S.L. Smalley, E.J.S.S.-B., H.-C.S., A.A.T. and N.W. PGC ASD Working Group: R.A.,
D.E.A., A.J.B., A.B., C.B., J.D. Buxbaum, A. Chakravarti, E.H.C., H.C., M.L.C., G.D.,
E.D., S.E., E.F., C.M.F., L. Gallagher, D.H.G., M. Gill, D.E.G., J.L.H., H.H., J.H., V.H.,
S.M.K., L. Klei, D.H. Ledbetter, C. Lord, J.K.L., E.M., S.M.M., C.L.M., W.M.M.,
A.P.M., D.M.-D.-L., E.M.M., M. Murtha, G.O., A.P., J.R.P., A.D.P., M.A.P.-V.,
J. Piven, F.P., K. Rehnstrm, K. Roeder, G.R., S.J.S., S.L. Santangelo, G.D.S., S.W.S.,
M. State, J.S. Sutcliffe, P. Szatmari, A.M.V., V.J.V., C.A.W., T.H.W., E.M.W., A.J.W.,
T.W.Y., B.D. and M.J.D. PGC BPD Working Group: S.M.P., D.A., H.A., O.A.A.,
A.A., L.B., J.A.B., J.D. Barchas, T.B.B., N.B., M. Bauer, F.B., S.E.B., W.B., D.H.R.B.,
C.S.B., M. Boehnke, G.B., R. Breuer, W.E.B., W.F.B., S. Caesar, K. Chambert,
S. Cichon, D.A.C., A. Corvin, W.H.C., D.W.C., R.D., F. Degenhardt, S. Djurovic,
F. Dudbridge, H.J.E., B.E., A.E.F., I.N.F., M. Flickinger, T.F., J.F., C.F., L.F., E.S.G.,
M. Gill, K.G.-S., E.K.G., T.A.G., D.G., W.G., H.G., M.L.H., M. Hautzinger, S. Herms,
M. Hipolito, P.A.H., C.M.H., S.J., E.G.J., I.J., L.J., R. Kandaswamy, J.L.K., G.K.K.,
D.L.K., P.K., M. Landn, N.L., M. Lathrop, J. Lawrence, W.B.L., M. Leboyer, P.H.L.,
J. Li, P.L., D.-Y.L., C. Liu, F.W.L., S.L., P.B.M., W.M., N.G.M., M. Mattheisen, K.M.,
M. Mattingsdal, K.A.M., P.M., M.G.M., A. McIntosh, R.M., A.W.M., F.J.M.,
A. McQuillin, S.M., I.M., F.M., G.W.M., J.L.M., G.M., D.W.M., V. Moskvina, P.M.,
T.W.M., W.J.M., B.M.-M., R.M.M., C.M.N., I.N., V.N., M.M.N., J.I.N., E.A.N., C.O.,
U.O., M.J.O., B.S.P., J.B.P., P.P., E.M.Q., S. Raychaudhuri, A. Reif, J.P.R., M. Rietschel,
D. Ruderfer, M. Schalling, A.F.S., W.A.S., N.J.S., T.G.S., J. Schumacher, M. Schwarz,
E.S., L.J.S., P.D.S., E.N.S., D.S.C., M. Steffens, J.S. Strauss, J. Strohmaier, S.S., R.C.T.,
F.T., J.T., J.B.V., S.J.W., T.F.W., S.H.W., W.X., A.H.Y., P.P.Z., P.Z., S. Zllner, J.R.K.,
P. Sklar, M.J.D., M.C.O. and N.C. PGC MDD Working Group: M.R.B., T. Bettecken,
E.B.B., D.H.R.B., D.I.B., G.B., R. Breuer, S. Cichon, W.H.C., I.W.C., D. Czamara,
E.J.D.G., F. Degenhardt, A.E.F., J.F., S.D.G., M. Gross, S.P.H., A.C.H., A.K.H.,
S. Herms, I.B.H., F.H., W.J.H., S. Hoefels, J.-J.H., M.I., I.J., L.J., J.-Y. T., J.A.K.,
M.A.K., A.K., W.B.L., D.F.L., C.M.L., D.-Y.L., S.L., D.J.M., P.A.F.M., W.M.,. N.G.M.,
M. Mattheisen, P.J.M., P.M., A. McIntosh, A.W.M., C.M.M., L.M., G.W.M., P.M.,
B.M.-M., W.A.N., M.M.N., D.R.N., B.W.P., M.L.P., J.B.P., M. Rietschel, W.A.S.,
T.G.S., J. Shi, S.I.S., S.L. Slager, J.H.S., M. Steffens, F.T., J.T., M.U., E.J.C.G.v.d.O.,
G.V.G., M.M.W., G.W., F.G.Z., P.F.S. and N.R.W. PGC SCZ Working Group:
S. Ripke, B.M.N., S.M.P., B.J.M., I.A., F.A., O.A.A., M.H.A., N.B., D.W.B., D.H.R.B.,
R. Bruggeman, N.G.B., W.F.B., W.C., R.M.C., K. Choudhury, S. Cichon, C.R.C.,
P.C., A. Corvin, D. Curtis, S. Datta, S. Djurovic, G.J.D., J.D., F. Dudbridge, A.F., R.F.,
N.B.F., M. Friedl, P.V.G., L. Georgieva, I.G., M. Gill, H.G., L.D.H., M.L.H., T.F.H.,
A.M.H., P.A.H., C.M.H., A.I., A.K.K, R.S.K., M.C.K., E.K., Y.K., G.K.K., B.K.,
L. Krabbendam, R. Krasucki, J. Lawrence, P.H.L., T.L., D.F.L., J.A.L., D.-Y.L.,
D.H. Linszen, P.K.E.M., W.M., A.K.M., M. Mattheisen, M. Mattingsdal, S.M.,
S.A.M., A. McIntosh, A. McQuillin, H.M., I.M., V. Milanova, D.W.M., V. Moskvina,
I.M.-G., M.M.N., C.O., A.O., L.O., R.A.O., M.J.O., C.N.P., M.T.P., B.S.P., J. Pimm,
D.P., V.P., D.J.Q., H.B.R., M. Rietschel, L.R., D. Ruderfer, D. Rujescu, A.R.S., T.G.S.,
J. Shi, J.M.S., D.S.C., T.S.S., S.T., J.V.O., P.M.V., T.W., S. Zammit, P. Sklar,
M.J.D., M.C.O., N.C., P.F.S. and K.S.K. PGC Cross-Disorder Group Working
Group: S.H.L., S. Ripke, B.M.N., S.M.P., R.H.P., A.T., A.F., M.C.N., J.I.N., B.W.P.,
M. Rietschel, T.G.S., N.C., S.L. Santangelo, P.F.S., J.W.S., K.S.K. and N.R.W.
989
a n a ly s i s
PGC Analysis Working Group: S.H.L., S. Ripke, B.M.N., S.M.P., V.A., E.M.B.,
P.H.L., S.E.M., M.C.N., D.P., M.J.D. and N.R.W.
COMPETING FINANCIAL INTERESTS
The authors declare no competing financial interests.
npg
Reprints and permissions information is available online at http://www.nature.com/

reprints/index.html.
1. Kendler, K.S. & Eaves, L.J. Psychiatric Genetics (Review of Psychiatry) (American
Psychiatric Association, Arlington, VA, 2005).
2. Tsuang, M. & Faraone, S. The Genetics of Mood Disorders (Johns Hopkins University
Press, Baltimore, MD, 1990).
3. Smoller, J.W. & Finn, C.T. Family, twin, and adoption studies of bipolar disorder.
Am. J. Med. Genet. C. Semin. Med. Genet. 123C, 4858 (2003).
4. Ronald, A., Simonoff, E., Kuntsi, J., Asherson, P. & Plomin, R. Evidence for
overlapping genetic influences on autistic and ADHD behaviours in a community
twin sample. J. Child Psychol. Psychiatry 49, 535542 (2008).
5. Rommelse, N.N., Franke, B., Geurts, H.M., Hartman, C.A. & Buitelaar, J.K. Shared
heritability of attention-deficit/hyperactivity disorder and autism spectrum disorder.
Eur. Child Adolesc. Psychiatry 19, 281295 (2010).
6. Lichtenstein, P., Carlstrom, E., Rastam, M., Gillberg, C. & Anckarsater, H. The
genetics of autism spectrum disorders and related neuropsychiatric disorders in
childhood. Am. J. Psychiatry 167, 13571363 (2010).
7. Rapoport, J., Chavez, A., Greenstein, D., Addington, A. & Gogtay, N. Autism
spectrum disorders and childhood-onset schizophrenia: clinical and biological
contributions to a relation revisited. J. Am. Acad. Child Adolesc. Psychiatry 48,
1018 (2009).
8. King, B.H. & Lord, C. Is schizophrenia on the autism spectrum? Brain Res. 1380,
3441 (2011).
9. Sullivan, P.F. et al. Family history of schizophrenia and bipolar disorder as risk
factors for autism. Arch. Gen. Psychiatry 69, 10991103 (2012).
10. Crespi, B., Stead, P. & Elliot, M. Comparative genomics of autism and schizophrenia.
Proc. Natl. Acad. Sci. USA 107, 17361741 (2010).
11. Mortensen, P.B., Pedersen, M.G. & Pedersen, C.B. Psychiatric family history and
schizophrenia risk in Denmark: which mental disorders are relevant? Psychol. Med.
40, 201210 (2010).
12. Faraone, S.V., Biederman, J. & Wozniak, J. Examining the comorbidity between
attention deficit hyperactivity disorder and bipolar disorder: a meta-analysis of
family-genetic studies. Am. J. Psychiatry 169, 12561266 (2012).
13. Cole, J., Ball, H.A., Martin, N.C., Scourfield, J. & McGuffin, P. Genetic overlap
between measures of hyperactivity/inattention and mood in children and adolescents.
J. Am. Acad. Child Adolesc. Psychiatry 48, 10941101 (2009).
14. Craddock, N., ODonovan, M.C. & Owen, M.J. Genes for schizophrenia and bipolar
disorder? Implications for psychiatric nosology. Schizophr. Bull. 32, 916 (2006).
15. Green, E.K. et al. The bipolar disorder risk allele at CACNA1C also confers risk of
recurrent major depression and of schizophrenia. Mol. Psychiatry 15, 10161022
(2010).
16. Williams, N.M. et al. Genome-wide analysis of copy number variants in attention
deficit/hyperactivity disorder confirms the role of rare variants and implicates
duplications at 15q13.3. Am. J. Psychiatry 169, 195204 (2012).
17. Manolio, T.A. Genomewide association studies and assessment of the risk of disease.
N. Engl. J. Med. 363, 166176 (2010).
18. Lee, S.H., Wray, N.R., Goddard, M.E. & Visscher, P.M. Estimating missing heritability
for disease from genome-wide association studies. Am. J. Hum. Genet. 88,
294305 (2011).
19. Yang, J. et al. Common SNPs explain a large proportion of the heritability for human
height. Nat. Genet. 42, 565569 (2010).
20. Lee, S.H., Yang, J., Goddard, M.E., Visscher, P.M. & Wray, N.R. Estimation of
pleiotropy between complex diseases using SNP-derived genomic relationships and
restricted maximum likelihood. Bioinformatics 28, 25402542 (2012).
21. Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium.
Genome-wide association study identifies five new schizophrenia loci. Nat. Genet.
43, 969976 (2011).
22. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genomewide association analysis of bipolar disorder identifies a new susceptibility locus
near ODZ4. Nat. Genet. 43, 977983 (2011).
23. Major Depressive Disorder Working Group of the Psychiatric GWAS Consortium.
A mega-analysis of genome-wide association studies for major depressive disorder.
Mol. Psychiatry 18, 497511 (2013).
24. Anney, R. et al. Individual common variants exert weak effects on the risk for
autism spectrum disorderspi. Hum. Mol. Genet. 21, 47814792 (2012).
25. Cross-Disorder Group of the Psychiatric GWAS Consortium. Genome-wide analysis
identifies loci with shared effects on five major psychiatric disorders. Lancet 381,
13711379 (2013).
26. Neale, B.M. et al. Meta-analysis of genome-wide association studies of attentiondeficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 49, 884897
(2010).
27. Stergiakouli, E. et al. Investigating the contribution of common genetic variants to
the risk and pathogenesis of ADHD. Am. J. Psychiatry 169, 186194 (2012).
990
28. Lionel, A.C. et al. Rare copy number variation discovery and cross-disorder
comparisons identify risk genes for ADHD. Sci. Transl. Med. 3, 95ra75 (2011).
29. Hinney, A. et al. Genome-wide association study in German patients with attention
deficit/hyperactivity disorder. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 156B,
888897 (2011).
30. Ribass, M. et al. Exploration of 19 serotoninergic candidate genes in adults and
children with attention-deficit/hyperactivity disorder identifies association for
5HT2A, DDC and MAOB. Mol. Psychiatry 14, 7185 (2009).
31. Lynch, M. & Walsh, B. Genetics and Analysis of Quantitative Traits (Sinauer
Associates, Sunderland, MA, 1998).
32. Purcell, S.M. et al. Common polygenic variation contributes to risk of schizophrenia
and bipolar disorder. Nature 460, 748752 (2009).
33. Lee, S.H., Goddard, M.E., Wray, N.R. & Visscher, P.M. A better coefficient of
determination for genetic profile analysis. Genet. Epidemiol. 36, 214224 (2012).
34. Raychaudhuri, S. et al. Accurately assessing the risk of schizophrenia conferred by
rare copy-number variation affecting genes with brain function. PLoS Genet. 6,
e1001097 (2010).
35. Lee, S.H. et al. Estimating the proportion of variation in susceptibility to
schizophrenia captured by common SNPs. Nat. Genet. 44, 247250 (2012).
36. Lubke, G.H. et al. Estimating the genetic variance of major depressive disorder due
to all single nucleotide polymorphisms. Biol. Psychiatry 72, 707709 (2012).
37. Klei, L. et al. Common genetic variants, acting additively, are a major source of
risk of autism. Mol. Autism 3, 9 (2012).
38. Browning, S.R. & Browning, B.L. Population structure can inflate SNP-based heritability
estimates. Am. J. Hum. Genet. 89, 191193, author reply 193195 (2011).
39. Yang, J. et al. Genome partitioning of genetic variation for complex traits using
common SNPs. Nat. Genet. 43, 519525 (2011).
40. Lee, S.H. et al. Estimation and partitioning of polygenic variation captured by
common SNPs for Alzheimers disease, multiple sclerosis and endometriosis. Hum.
Mol. Genet. 22, 832841 (2013).
41. Constantino, J.N. & Todd, R.D. Intergenerational transmission of subthreshold
autistic traits in the general population. Biol. Psychiatry 57, 655660 (2005).
42. Franke, A. et al. Genome-wide meta-analysis increases to 71 the number of confirmed
Crohns disease susceptibility loci. Nat. Genet. 42, 11181125 (2010).
43. Loftus, E.V. Jr. et al. Increased risks of developing anxiety and depression in young
patients with Crohns disease. Am. J. Gastroenterol. 106, 16701677 (2011).
44. Kohane, I.S. et al. The co-morbidity burden of children and young adults with
autism spectrum disorders. PLoS ONE 7, e33224 (2012).
45. Benach, J.L., Li, E. & McGovern, M.M. A microbial association with autism.
mBio 3, e0001912 (2012).
46. Wray, N.R., Lee, S.H. & Kendler, K.S. Impact of diagnostic misclassification on
estimation of genetic correlations using genome-wide genotypes. Eur. J. Hum.
Genet. 20, 668674 (2012).
47. Bromet, E.J. et al. Diagnostic shifts during the decade following first admission for
psychosis. Am. J. Psychiatry 168, 11861194 (2011).
48. Laursen, T.M., Agerbo, E. & Pedersen, C.B. Bipolar disorder, schizoaffective
disorder, and schizophrenia overlap: a new comorbidity index. J. Clin. Psychiatry
70, 14321438 (2009).
49. Tsuang, M.T., Woolson, R.F., Winokur, G. & Crowe, R.R. Stability of psychiatric
diagnosis. Schizophrenia and affective disorders followed up over a 30- to 40-year
period. Arch. Gen. Psychiatry 38, 535539 (1981).
50. Visscher, P.M., Brown, M.A., McCarthy, M.I. & Yang, J. Five years of GWAS discovery.
Am. J. Hum. Genet. 90, 724 (2012).
51. Wray, N.R. et al. Genome-wide association study of major depressive disorder:
new results, meta-analysis, and lessons learned. Mol. Psychiatry 17, 3648
(2012).
52. Falconer, D. & Mackay, T. Introduction to Quantitative Genetics 4th edn. (Longman
Scientific & Technical, Harlow, UK, 1996).
53. Van Snellenberg, J.X. & de Candia, T. Meta-analytic evidence for familial
coaggregation of schizophrenia and bipolar disorder. Arch. Gen. Psychiatry 66,
748755 (2009).
54. Lichtenstein, P. et al. Common genetic determinants of schizophrenia and bipolar disorder
in Swedish families: a population-based study. Lancet 373, 234239 (2009).
55. McGuffin, P. et al. The heritability of bipolar affective disorder and the genetic
relationship to unipolar depression. Arch. Gen. Psychiatry 60, 497502
(2003).
56. Moreno-De-Luca, D. et al. Deletion 17q12 is a recurrent copy number variant that confers
high risk of autism and schizophrenia. Am. J. Hum. Genet. 87, 618630 (2010).
57. Stankiewicz, P. & Lupski, J.R. Structural variation in the human genome and its
role in disease. Annu. Rev. Med. 61, 437455 (2010).
58. Nijmeijer, J.S. et al. Identifying loci for the overlap between attention-deficit/
hyperactivity disorder and autism spectrum disorder using a genome-wide QTL
linkage approach. J. Am. Acad. Child Adolesc. Psychiatry 49, 675685
(2010).
59. Mulligan, A. et al. Autism symptoms in attention-deficit/hyperactivity disorder: a
familial trait which correlates with conduct, oppositional defiant, language and
motor disorders. J. Autism Dev. Disord. 39, 197209 (2009).
60. Ripke, S.A. et al. Genome-wide association analysis identifies 13 new risk loci for
schizophrenia. Nat. Genet. (in the press).
61. Sullivan, P.F., Daly, M.J. & ODonovan, M. Genetic architectures of psychiatric
disorders: the emerging picture and its implications. Nat. Rev. Genet. 13, 537551
(2012).
npg
a n a ly s i s
S Hong Lee1, Stephan Ripke2,3, Benjamin M Neale2,3, Stephen V Faraone4,5, Shaun M Purcell2,3,6, Roy H Perlis3,7,
Bryan J Mowry1,8, Anita Thapar9,10, Michael E Goddard11,12, John S Witte13, Devin Absher14, Ingrid Agartz15,16,
Huda Akil17, Farooq Amin18, Ole A Andreassen15,19, Adebayo Anjorin20, Richard Anney21, Verneri Anttila2,
Dan E Arking22, Philip Asherson23, Maria H Azevedo24, Lena Backlund25, Judith A Badner26, Anthony J Bailey27,
Tobias Banaschewski28, Jack D Barchas29, Michael R Barnes30, Thomas B Barrett31, Nicholas Bass20,
Agatino Battaglia32, Michael Bauer33, Mnica Bays34, Frank Bellivier3538, Sarah E Bergen3,7,39,
Wade Berrettini40, Catalina Betancur4143, Thomas Bettecken44, Joseph Biederman45, Elisabeth B Binder44,
Donald W Black46, Douglas H R Blackwood47, Cinnamon S Bloss48,49, Michael Boehnke50,51,
Dorret I Boomsma5254, Gerome Breen23,55, Ren Breuer56, Richard Bruggeman57, Paul Cormican21,
Nancy G Buccola58, Jan K Buitelaar59, William E Bunney60, Joseph D Buxbaum61, William F Byerley62,63,
Enda M Byrne1, Sian Caesar64, Wiepke Cahn65, Rita M Cantor66, Miguel Casas67,68, Aravinda Chakravarti22,
Kimberly Chambert3, Khalid Choudhury20, Sven Cichon6972, C Robert Cloninger73, David A Collier23,
Edwin H Cook74, Hilary Coon75, Bru Cormand7678, Aiden Corvin21, William H Coryell46, David W Craig79,
Ian W Craig23, Jennifer Crosbie80, Michael L Cuccaro81, David Curtis82, Darina Czamara44,83, Susmita Datta84,
Geraldine Dawson8587, Richard Day88, Eco J De Geus5254, Franziska Degenhardt69,71, Srdjan Djurovic15,89,
Gary J Donohoe21, Alysa E Doyle90, Jubao Duan91, Frank Dudbridge92, Eftichia Duketis93, Richard P Ebstein94,
Howard J Edenberg95,96, Josephine Elia40,97, Sean Ennis98, Bruno Etain35,38,99,100, Ayman Fanous101,102,
Anne E Farmer23, I Nicol Ferrier103, Matthew Flickinger50,51, Eric Fombonne104,105, Tatiana Foroud96,
Josef Frank56, Barbara Franke59, Christine Fraser9,10, Robert Freedman106, Nelson B Freimer107,
Christine M Freitag93, Marion Friedl108, Louise Frisn25, Louise Gallagher21, Pablo V Gejman91,
Lyudmila Georgieva9,10, Elliot S Gershon26, Daniel H Geschwind109,110, Ina Giegling108, Michael Gill21,
Scott D Gordon111, Katherine Gordon-Smith9,64, Elaine K Green112, Tiffany A Greenwood113,
Dorothy E Grice114,115, Magdalena Gross116, Detelina Grozeva9, Weihua Guan50,51,117, Hugh Gurling20,
Lieuwe De Haan118, Jonathan L Haines119, Hakon Hakonarson120,121, Joachim Hallmayer122,
Steven P Hamilton62, Marian L Hamshere9,123, Thomas F Hansen124,125, Annette M Hartmann108,
Martin Hautzinger126, Andrew C Heath73, Anjali K Henders111, Stefan Herms69,72, Ian B Hickie127,
Maria Hipolito128, Susanne Hoefels116, Peter A Holmans9,123, Florian Holsboer44, Witte J Hoogendijk129,
Jouke-Jan Hottenga52,54, Christina M Hultman39, Vanessa Hus130, Andrs Ingason124,125, Marcus Ising44,
Stphane Jamain35,38,99,100, Edward G Jones131,256, Ian Jones9,10, Lisa Jones64, Jung-Ying Tzeng132,
Anna K Khler39, Ren S Kahn65, Radhika Kandaswamy20, Matthew C Keller133, James L Kennedy134,
Elaine Kenny21, Lindsey Kent135, Yunjung Kim136, George K Kirov9,10, Sabine M Klauck137, Lambertus Klei138,
James A Knowles139, Martin A Kohli44, Daniel L Koller96, Bettina Konte108, Ania Korszun140,
Lydia Krabbendam141, Robert Krasucki20, Jonna Kuntsi23, Phoenix Kwan50,51, Mikael Landn39,142,
Niklas Lngstrm39, Mark Lathrop143, Jacob Lawrence20, William B Lawson128, Marion Leboyer35,38,99,100,
David H Ledbetter144, Phil H Lee7, Todd Lencz145147, Klaus-Peter Lesch148,149, Douglas F Levinson150,
Cathryn M Lewis23, Jun Li151, Paul Lichtenstein39, Jeffrey A Lieberman152, Dan-Yu Lin153, Don H Linszen154,
Chunyu Liu155, Falk W Lohoff40, Sandra K Loo107,156, Catherine Lord157, Jennifer K Lowe109,110,
Susanne Lucae44, Donald J MacIntyre47, Pamela A F Madden73, Elena Maestrini158, Patrik K E Magnusson39,
Pamela B Mahon159, Wolfgang Maier116, Anil K Malhotra145147, Shrikant M Mane160, Christa L Martin144,
Nicholas G Martin111, Manuel Mattheisen71,125,161,162, Keith Matthews88, Morten Mattingsdal15,163,
Steven A McCarroll3, Kevin A McGhee47, James J McGough164, Patrick J McGrath152, Peter McGuffin23,
Melvin G McInnis165, Andrew McIntosh47,166, Rebecca McKinney113, Alan W McLean47,166,
Francis J McMahon167, William M McMahon75, Andrew McQuillin20, Helena Medeiros139, Sarah E Medland111,
Sandra Meier56, Ingrid Melle15,19, Fan Meng17, Jobst Meyer168, Christel M Middeldorp52,54, Lefkos Middleton169,
Vihra Milanova170, Ana Miranda171, Anthony P Monaco172,173, Grant W Montgomery111, Jennifer L Moran3,
Daniel Moreno-De-Luca174, Gunnar Morken175,176, Derek W Morris21, Eric M Morrow177,178,
Valentina Moskvina9,123, Pierandrea Muglia179, Thomas W Mhleisen69,71,180, Walter J Muir47,166,256,
Bertram Mller-Myhsok44,83, Michael Murtha181, Richard M Myers14, Inez Myin-Germeys141,
Michael C Neale102, Stan F Nelson107, Caroline M Nievergelt113, Ivan Nikolov9,10, Vishwajit Nimgaonkar182,183,
Willem A Nolen184, Markus M Nthen69,71, John I Nurnberger96,185, Evaristus A Nwulia128, Dale R Nyholt111,
Colm ODushlaine3, Robert D Oades186, Ann Olincy106, Guiomar Oliveira24,187, Line Olsen124,125,
991
npg
a n a ly s i s
Roel A Ophoff107,188,189, Urban Osby25, Michael J Owen9,10, Aarno Palotie190, Jeremy R Parr103,
Andrew D Paterson191,192, Carlos N Pato139, Michele T Pato139, Brenda W Penninx53,54,193, Michele L Pergadia73,
Margaret A Pericak-Vance81, Benjamin S Pickard47,166, Jonathan Pimm20, Joseph Piven87, Danielle Posthuma194196,
James B Potash46, Fritz Poustka93, Peter Propping71, Vinay Puri20, Digby J Quested197, Emma M Quinn21,
Josep Antoni Ramos-Quiroga67,68, Henrik B Rasmussen124,125, Soumya Raychaudhuri2,3, Karola Rehnstrm190,
Andreas Reif198, Marta Ribass67,199, John P Rice200, Marcella Rietschel56, Kathryn Roeder201,
Herbert Roeyers202, Lizzy Rossin3, Aribert Rothenberger203, Guy Rouleau204, Douglas Ruderfer6,
Dan Rujescu108, Alan R Sanders91, Stephan J Sanders174,181,205,206, Susan L Santangelo207,208,
Joseph A Sergeant209, Russell Schachar80, Martin Schalling25, Alan F Schatzberg210, William A Scheftner211,
Gerard D Schellenberg212, Stephen W Scherer213, Nicholas J Schork48,214, Thomas G Schulze159,215,
Johannes Schumacher71, Markus Schwarz216, Edward Scolnick3, Laura J Scott50,51, Jianxin Shi217,
Paul D Shilling113, Stanley I Shyn218, Jeremy M Silverman115, Susan L Slager219, Susan L Smalley107,156,
Johannes H Smit53,193, Erin N Smith48,214, Edmund J S Sonuga-Barke202,220, David St. Clair221,
Matthew State174,181,205, Michael Steffens222, Hans-Christoph Steinhausen223225, John S Strauss226,
Jana Strohmaier56, T Scott Stroup227, James S Sutcliffe228, Peter Szatmari229231, Szabocls Szelinger79,
Srinivasa Thirumalai232, Robert C Thompson17, Alexandre A Todorov73, Federica Tozzi179, Jens Treutlein56,
Manfred Uhr44, Edwin J C G van den Oord233, Gerard Van Grootheest53,193, Jim Van Os141, Astrid M Vicente234236,
Veronica J Vieland237, John B Vincent226, Peter M Visscher1,238, Christopher A Walsh239242,
Thomas H Wassink46, Stanley J Watson17, Myrna M Weissman243, Thomas Werge124,125,244,
Thomas F Wienker245, Ellen M Wijsman246,247, Gonneke Willemsen52,53, Nigel Williams9,10,
A Jeremy Willsey181,205, Stephanie H Witt56, Wei Xu192, Allan H Young103,248, Timothy W Yu249,
Stanley Zammit9,10, Peter P Zandi250, Peng Zhang50,51,165, Frans G Zitman251, Sebastian Zllner50,51,165,
International Inflammatory Bowel Disease Genetics Consortium (IIBDGC)252, Bernie Devlin138,
John R Kelsoe113,253, Pamela Sklar6, Mark J Daly2,3, Michael C ODonovan9,10, Nicholas Craddock9,10,
Patrick F Sullivan136, Jordan W Smoller3,7, Kenneth S Kendler102,254,255,257 & Naomi R Wray1,257
1The
University of Queensland, Queensland Brain Institute, Brisbane, Queensland, Australia. 2Analytic and Translational Genetics Unit, Massachusetts General
Hospital and Harvard Medical School, Boston, Massachusetts, USA. 3Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge,
Massachusetts, USA. 4Department of Psychiatry, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, USA. 5Department of
Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, New York, USA. 6Division of Psychiatric Genomics, Department of Psychiatry, Icahn School
of Medicine at Mount Sinai, New York, New York, USA. 7Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts,
USA. 8Queensland Centre for Mental Health Research, Wacol, Queensland, Australia. 9Medical Research Council (MRC) Centre for Neuropsychiatric Genetics and
Genomics, Cardiff University School of Medicine, Cardiff, UK. 10Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University School of
Medicine, Cardiff, UK. 11Biosciences Research Division, Department of Environment and Primary Industries Victoria, Melbourne, Victoria, Australia. 12Faculty of Land
and Environment, University of Melbourne, Melbourne, Victoria, Australia. 13Department of Epidemiology and Biostatistics, University of California, San Francisco,
San Francisco, California, USA. 14HudsonAlpha Institute of Biotechnology, Huntsville, Alabama, USA. 15KG Jebsen Centre for Psychosis Research, Institute of Clinical
Medicine, University of Oslo, Oslo, Norway. 16Department of Research, Diakonhjemmet Hospital, Oslo, Norway. 17Molecular Psychiatry Laboratory, Molecular and
Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, Michigan, USA. 18Department of Psychiatry and Behavioral Sciences, Atlanta Veterans Affairs
Medical Center, Emory University, Atlanta, Georgia, USA. 19Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 20Mental Health Sciences
Unit, University College London, London, UK. 21Department of Psychiatry, Trinity College Dublin, Dublin, Ireland. 22McKusick-Nathans Institute of Genetic Medicine,
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 23MRC Social, Genetic and Developmental Psychiatry (SGDP) Centre, The Institute of
Psychiatry, Kings College London, London, UK. 24Faculty of Medicine, University of Coimbra, Coimbra, Portugal. 25Department of Molecular Medicine and Surgery,
Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. 26Department of Psychiatry, University of Chicago, Chicago, Illinois, USA. 27Department of
Psychiatry, University of British Columbia, Vancouver, British Columbia, Canada. 28Department of Child and Adolescent Psychiatry and Psychotherapy, Central
Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. 29Department of Psychiatry, Weill Medical College, Cornell
University, New York, New York, USA. 30GlaxoSmithKline, London, UK. 31Portland Veterans Affairs Medical Center, Portland, Oregon, USA. 32Stella Maris Institute for
Child and Adolescent Neuropsychiatry, Calambrone, Pisa, Italy. 33Department of Psychiatry and Psychotherapy, Carl Gustav Carus University Hospital, Dresden,
Germany. 34Centro Nacional de Anlisis Genmico (CNAG), Parc Cientfic de Barcelona (PCB), Barcelona, Spain. 35Institut National de la Sant et de la Recherche
Mdicale (INSERM) U955, Psychiatrie Gntique, Crteil, France. 36Universit Denis Diderot, Paris, France. 37Assistance PubliqueHpitaux de Paris (AP-HP),
Groupe Hospitalier Saint-Louis, Lariboisiere, F Widal, Departement de Psychiatrie, Paris, France. 38ENBREC (European Network of Bipolar Research Expert Centres)
Group, Fondation FondaMental, Crteil, France. 39Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. 40Department of
Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 41INSERM U952, Paris, France. 42Centre National de la Recherche Scientifique (CNRS)
Unit Mixte de Recherche (UMR) 7224, Paris, France. 43Universit Pierre et Marie Curie, Paris, France. 44Max Planck Institute of Psychiatry, Munich, Germany.
45Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital and Harvard Medical School, Boston,
Massachusetts, USA. 46Department of Psychiatry, University of Iowa, Iowa City, Iowa, USA. 47Division of Psychiatry, University of Edinburgh, Royal Edinburgh
Hospital, Edinburgh, UK. 48The Scripps Translational Science Institute, La Jolla, California, USA. 49Scripps Health, La Jolla, California, USA. 50Department of
Biostatistics, School of Public Health, University of Michigan, Ann Arbor, Michigan, USA. 51Center for Statistical Genetics, School of Public Health, University of
Michigan, Ann Arbor, Michigan, USA. 52Department of Biological Psychology, VU University, Amsterdam, The Netherlands. 53EMGO+ (ExtraMuraalGeneeskundig
Onderzoek) Institute for Health and Care Research, Amsterdam, The Netherlands. 54Neuroscience Campus Amsterdam, Amsterdam, The Netherlands. 55National
Institute of Heath Research (NIHR) Biomedical Research Centre for Mental Health, South London, London, UK and Maudsley National Health Service (NHS) Trust and
Institute of Psychiatry, London, UK. 56Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg
University, Mannheim, Germany. 57Department of Psychiatry, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 58School of
Nursing, Louisiana State University Health Sciences Center, New Orleans, Louisiana, USA. 59Department of Cognitive Neuroscience, Donders Institute for Brain,
992
npg
a n a ly s i s
Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands. 60Department of Psychiatry and Human Behavior, University of California
Irvine, Irvine, California, USA. 61Seaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York,
New York, USA. 62Department of Psychiatry, University of California, San Francisco, San Francisco, California, USA. 63NCIRE (Northern California Institute of Q
Research and Education), San Francisco, California, USA. 64Department of Psychiatry, Birmingham University, Birmingham, UK. 65Department of Psychiatry, Rudolf
Magnus Institute of Neuroscience, University Medical Center, Utrecht, The Netherlands. 66David Geffen School of Medicine, University of California, Los Angeles, Los
Angeles, California, USA. 67Department of Psychiatry, Hospital Universitari Vall dHebron, CIBERSAM (Centro de Investigacin Biomdica en el Area de Salud
Mental), Barcelona, Spain. 68Department of Psychiatry and Legal Medicine, Universitat Autnoma de Barcelona, Barcelona, Spain. 69Department of Genomics, Life &
Brain Center, University of Bonn, Bonn, Germany. 70Institute of Neuroscience and Medicine (INM-1), Research Center Jlich, Jlich, Germany. 71Institute of Human
Genetics, University of Bonn, Bonn, Germany. 72Division of Medical Genetics, Department of Biomedicine, University of Basel, Basel, Switzerland. 73Department of
Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA. 74Department of Psychiatry, Institute for Juvenile Research, University of Illinois,
Chicago, Illinois, USA. 75Department of Psychiatry, University of Utah, Salt Lake City, Utah, USA. 76Departament de Gentica, Facultat de Biologia, Universitat de
Barcelona, Barcelona, Spain. 77Biomedical Network Research Centre on Rare Diseases (CIBERER), Barcelona, Spain. 78Institut de Biomedicina de la Universitat de
Barcelona (IBUB), Barcelona, Spain. 79The Translational Genomics Research Institute, Phoenix, Arizona, USA. 80Neurosciences and Mental Health Program, The
Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. 81John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida,
USA. 82East London NHS Foundation Trust, Queen Mary, University of London, London, UK. 83Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
84Genetics Institute, University College London, London, UK. 85Autism Speaks, New York, New York, USA. 86Department of Psychiatry, University of North Carolina at
Chapel Hill, Chapel Hill, North Carolina, USA. 87Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, North
Carolina, USA. 88Division of Neuroscience, Medical Research Institute, University of Dundee, Ninewells Hospital & Medical School, Dundee, UK. 89Department of
Medical Genetics, Oslo University Hospital, Oslo, Norway. 90Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical
School, Boston, Massachusetts, USA. 91Department of Psychiatry and Behavioral Sciences, NorthShore University Health System and University of Chicago, Evanston,
Illinois, USA. 92Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK. 93Department of Child and
Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Frankfurt, Germany. 94Psychology Department, National University of
Singapore, Singapore. 95Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA. 96Department of
Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA. 97AI Dupont Hospital for Children, University of Pennsylvania,
Philadelphia, Pennsylvania, USA. 98School of Medicine, Medical Science University College, Dublin, Ireland. 99Universit Paris Est, Facult de Mdecine, Crteil,
France. 100AP-HP, Hpital H MondorA Chenevier, Dpartement de Psychiatrie, Crteil, France. 101Department of Psychiatry, Georgetown University School of
Medicine, Washington, DC, USA. 102Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, USA.
103Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK. 104Department of Psychiatry, Oregon Health & Science University, Portland, Oregon,
USA. 105Institute for Development & Disability, Oregon Health & Science University, Portland, Oregon, USA. 106Department of Psychiatry, University of Colorado
Denver, Aurora, Colorado, USA. 107Center for Neurobehavioral Genetics, University of California, Los Angeles, Los Angeles, California, USA. 108Department of
Psychiatry, University of Halle, Halle, Germany. 109Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles,
California, USA. 110Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles,
California, USA. 111Queensland Institute of Medical Research, Brisbane, Queensland, Australia. 112Department of Biomedical and Biological Sciences, Plymouth
University, Plymouth, UK. 113Department of Psychiatry, University of California, San Diego, La Jolla, California, USA. 114Division of Tics, OCD and Related Disorders,
Icahn School of Medicine at Mount Sinai, New York, New York, USA. 115Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York,
USA. 116Department of Psychiatry, University of Bonn, Bonn, Germany. 117Division of Biostatistics, University of Minnesota, Minneapolis, Minnesota, USA.
118Department of Psychiatry, Academic Medical Centre, University of Amsterdam The Netherlands. 119Center for Human Genetics Research, Vanderbilt University
Medical Center, Nashville, Tennessee, USA. 120The Center for Applied Genomics, Division of Human Genetics, The Childrens Hospital of Philadelphia, Philadelphia,
Pennsylvania, USA. 121Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA. 122Department of Psychiatry,
School of Medicine, Stanford University, Stanford, California, USA. 123Biostatistics and Bioinformatics Unit, Cardiff University, Cardiff, UK. 124Institute of Biological
Psychiatry, Copenhagen University Hospital, Roskilde, Denmark. 125The Lundbeck Initiative for Integrative Psychiatric Research, iPSYCH, Roskilde, Denmark.
126Department of Clinical and Developmental Psychology, Eberhard Karls University of Tbingen, Tbingen, Germany. 127Brain and Mind Research Institute,
University of Sydney, Sydney, New South Wales, Australia. 128Department of Psychiatry and Behavioral Sciences, Howard University College of Medicine, Washington,
DC, USA. 129Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands. 130Department of Psychology, University of Michigan, Ann Arbor,
Michigan, USA. 131Center for Neuroscience, University of California, Davis, Davis, California, USA. 132Bioinformatics Research Center, North Carolina State
University, Raleigh, North Carolina, USA. 133Department of Psychology, University of Colorado, Boulder, Colorado, USA. 134Psychiatric Neurogenetics Section, Centre
for Addiction and Mental Health, Toronto, Ontario, Canada. 135School of Medicine, University of St Andrews, St Andrews, UK. 136Department of Genetics, University
of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 137Division of Molecular Genome Analysis, German Cancer Research Center (DKFZ), Heidelberg,
Germany. 138Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA. 139Department of Psychiatry, Zilkha Neurogenetic
Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA. 140Wolfson Institute of Preventitive Medicine, Queen Mary
University of London, London, UK. 141Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, South Limburg Mental Health Research
and Teaching Network, Maastricht, The Netherlands. 142Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden. 143Centre National
de Genotypage, Evry, France. 144Geisinger Health System, Autism and Developmental Medicine Institute, Danville, Pennsylvania, USA. 145Department of Psychiatry,
Division of Research, The Zucker Hillside Hospital Division of the North Shore, Long Island Jewish Health System, Glen Oaks, New York, USA. 146Center for
Psychiatric Neuroscience, The Feinstein Institute of Medical Research, Manhasset, New York, USA. 147Department of Psychiatry and Behavioral Science, Albert
Einstein College of Medicine of Yeshiva University, Bronx, New York, USA. 148Division of Molecular Psychiatry, ADHD Clinical Research Unit, Department of
Psychiatry, Psychosomatics and Psychotherapy, University of Wrzburg, Wrzburg, Germany. 149Department of Psychiatry and Psychology, School for Mental Health
and Neuroscience (MHENS), Maastricht University, Maastricht, The Netherlands. 150Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford,
California, USA. 151Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA. 152New York State Psychiatric Institute, Columbia University,
New York, New York, USA. 153Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 154Department of Psychiatry,
Academic Medical Centre University of Amsterdam, Amsterdam, The Netherlands. 155Department of Psychiatry, Institute of Human Genetics, University of Illinois at
Chicago, Chicago, Illinois, USA. 156Department of Psychiatry and Biobehavioral Science, University of California, Los Angeles, Los Angeles, California, USA. 157Center
for Autism and the Developing Brain, Weill Cornell Medical College, White Plains, New York, USA. 158Department of Pharmacy and Biotechnology, University of
Bologna, Bologna, Italy. 159Department of Psychiatry & Behavioral Sciences, Johns Hopkins University, Baltimore, Maryland, USA. 160Yale Center for Genome
Analysis, Orange, Connecticut, USA. 161Department of Biomedicine, Aarhus University, Aarhus, Denmark. 162Department of Genomic Mathematics, University of
Bonn, Bonn, Germany. 163Srlandet Hospital, Kristiansand, Norway. 164Child and Adolescent Psychiatry, Semel Institute, David Geffen School of Medicine, University
of California, Los Angeles, Los Angeles, California, USA. 165Department of Psychiatry, University of Michigan, Ann Arbor, Michigan, USA. 166Molecular Medicine
Centre, University of Edinburgh, Edinburgh, UK. 167National Institute of Mental Health, US National Institutes of Health, Bethesda, Maryland, USA. 168Department of
Neurobehavioral Genetics, Trier University, Trier, Germany. 169Neuroepidemiology and Ageing Research, School of Public Health, Imperial College London, London,
UK. 170Department of Psychiatry, First Psychiatric Clinic, Alexander University Hospital, Sofia, Bulgaria. 171Department of Developmental and Educational
Psychology, University of Valencia, Valencia, Spain. 172Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. 173Office of the President, Tufts
University, Medford, Massachusetts, USA. 174Department of Psychiatry, Yale University, New Haven, Connecticut, USA. 175Department of Psychiatry, St. Olavs
Hospital, Trondheim, Norway. 176Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. 177Department of Molecular
Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA. 178Department of Psychiatry and Human Behavior, Brown University,
Providence, Rhode Island, USA. 179Neurosciences Centre of Excellence in Drug Discovery, GlaxoSmithKline Research and Development, Verona, Italy. 180Life & Brain
Center, University of Bonn, Bonn, Germany. 181Child Study Center, Yale University, New Haven, Connecticut, USA. 182Department of Psychiatry, University of
Pittsburgh, Pittsburgh, Pennsylvania, USA. 183Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. 184Department of Psychiatry,
Groningen University Medical Center, Groningen, The Netherlands. 185Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA.
993
186Clinic for Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany. 187Research and Clinical Training Department,
Pediatric Hospital, Centro Hospitalar e Universitrio Coimbra, Coimbra, Portugal. 188Department of Human Genetics, University of California, Los Angeles, Los
Angeles, California, USA. 189Department of Psychiatry, University Medical Center Utrecht, Utrecht, The Netherlands. 190Sanger Institute, Hinxton, Cambridge, UK.
191Program in Genetics and Genomic Biology, The Hospital for Sick Children, Toronto, Ontario, Canada. 192Dalla Lana School of Public Health, University of Toronto,
Toronto, Ontario, Canada. 193Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands. 194Department of Functional Genomics, VU
University, Amsterdam, The Netherlands. 195Department of Clinical Genetics, VU Medical Center, Amsterdam, The Netherlands. 196Department of Child and
Adolescent Psychiatry, Erasmus University Medical Center, Rotterdam, The Netherlands. 197Academic Department of Psychiatry, University of Oxford, Oxford, UK.
198Department of Psychiatry, University of Wrzburg, Wrzburg, Germany. 199Psychiatric Genetics Unit, Vall dHebron Research Institute, Barcelona, Spain.
200Division of Biostatistics, Washington University School of Medicine, St. Louis, Missouri, USA. 201Department of Statistics, Carnegie Mellon University, Pittsburgh,
Pennsylvania, USA. 202Department of Experimental Clinical & Health Psychology, Ghent University, Ghent, Belgium. 203Child and Adolescent Psychiatry, University
Medicine Gttingen, Gttingen, Germany. 204Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada. 205Department of Genetics,
Yale University, New Haven, Connecticut, USA. 206Program on Neurogenetics, Yale University, New Haven, Connecticut, USA. 207Department of Psychiatry, Maine
Medical Center, Portland, Maine, USA. 208Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA. 209Department of Clinical
Neuropsychology, VU University, Amsterdam, The Netherlands. 210Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Palo
Alto, California, USA. 211Rush Ambulatory Behavioral Health, Rush University Medical Center, Chicago, Illinois, USA. 212Department of Pathology and Laboratory
Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 213The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
214The Scripps Research Institute, La Jolla, California, USA. 215Department of Psychiatry & Psychotherapy, University of Gttingen, Gttingen, Germany.
216Psychiatric Center Nordbaden, Wiesloch, Germany. 217Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
218Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington, USA. 219Mayo Clinic, Rochester, Minnesota, USA.
220Developmental Brain & Behaviour Laboratory, Academic Unit of Psychology, University of Southampton, Southampton, UK. 221Institute of Medical Sciences,
University of Aberdeen, Foresterhill, Aberdeen, UK. 222Research Department, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany. 223Research
Unit of Child and Adolescent Psychiatry, Aalborg University Hospital, Aalborg, Denmark. 224Clinical Psychology and Epidemiology, University of Basel, Basel,
Switzerland. 225Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland. 226Molecular Neuropsychiatry and Development Laboratory,
Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 227Department of Psychiatry, Columbia University, New York, New York, USA. 228Vanderbilt Brain
Institute, Vanderbilt University, Nashville, Tennessee, USA. 229Department of Psychiatry, University of Toronto, Toronto, Ontario Canada. 230Neurosciences and Mental
Health Program, Hospital for Sick Children, Toronto, Ontario Canada. 231Centre for Addiction and Mental Health, Toronto, Ontario, Canada. 232Oxford Health NHS
Foundation Trust, Marlborough House Secure Unit, Milton Keynes, UK. 233Center for Biomarker Research and Personalized Medicine, Virginia Commonwealth
University, Richmond, Virginia, USA. 234Instituto Nacional de Saude Dr Ricardo Jorge, Lisbon, Portugal. 235BioFIGCenter for Biodiversity, Functional and Integrative
Genomics, Campus da FCUL, Campo Grande, Lisbon, Portugal. 236Instituto Gulbenkian de Cencia, Lisbon, Portugal. 237Battelle Center for Mathematical Medicine,
Nationwide Childrens Hospital, Columbus, Ohio, USA. 238The University of Queensland, Diamantina Institute, Brisbane, Queensland, Australia. 239Howard Hughes
Medical Institute, Childrens Hospital Boston, Boston, Massachusetts, USA. 240Division of Genetics, Childrens Hospital Boston, Boston, Massachusetts, USA.
241Department of Neurology, Harvard Medical School Center for Life Sciences, Boston, Massachusetts, USA. 242Department of Pediatrics, Harvard Medical School
Center for Life Sciences, Boston, Massachusetts, USA. 243Columbia University College of Physicians and Surgeons, New York, New York, USA. 244Faculty of Health
and Medical Science, University of Copenhagen, Copenhagen, Denmark. 245Institute of Medical Biometry, University of Bonn, Bonn, Germany. 246Department of
Biostatistics, University of Washington, Seattle, Washington, USA. 247Department of Medicine, University of Washington, Seattle, Washington, USA. 248Centre for
Affective Disorders, Institute of Psychiatry, Kings College London, London, UK. 249Division of Genetics, Childrens Hospital Boston, Harvard Medical School, Boston,
Massachusetts, USA. 250Department of Mental Health, Johns Hopkins University, Baltimore, Maryland, USA. 251Department of Psychiatry, Leiden University Medical
Center, Leiden, The Netherlands. 252A list of members appears in the Supplementary Note. 253Department of Psychiatry, Special Treatment and Evaluation Program
(STEP), Veterans Affairs San Diego Healthcare System, San Diego, California, USA. 254Department of Human and Molecular Genetics, Virginia Commonwealth
University, Richmond, Virginia, USA. 255Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, USA. 256Deceased. 257These authors
contributed equally to this work. Correspondence should be addressed to N.R.W. (naomi.wray@uq.edu.au).
npg
a n a ly s i s
994
npg
ONLINE METHODS
Data and quality control. A summary of the data available for analysis is listed
in Table 1 and comprise data used in the PGCCross-Disorder Group analysis25 together with newly available ADHD samples2730. Data upload to the
PGC central server follows strict guidelines to ensure local ethics committee
approval for all contributed data (PGC; see URLs). Data from all study cohorts
were processed through the stringent PGC pipeline25. Imputation of autosomal
SNPs used CEU (Utah residents of Northern and Western European ancestry)
and TSI (Toscani in Italia) HapMap Phase 3 data as the reference panel21.
For each analysis (univariate or bivariate), we retained only SNPs that had
MAF of >0.01 and imputation R2 of >0.6 in all contributing cohort subsamples
(imputation cohorts). Different quality control strategies were investigated
in detail for the raw and PGC imputed genotyped data of the International
Schizophrenia Consortium, a subset of the PGC schizophrenia sample35. The
Crohns disease samples from IIBDGC42 were processed through the same
quality control and imputation pipeline as the PGC data, generating a data set
of 5,054 cases and 11,496 controls from 6 imputation cohorts.
In each analysis, individuals were excluded to ensure that all cases and
controls were completely unrelated in the classical sense, so that no pairs
of individuals had a genome-wide similarity relationship greater than 0.05
(equivalent to about second cousins). This procedure removed ancestry outliers (over and above those already removed in the PGC quality control pipeline; Supplementary Fig. 2) and ensured that overlapping control sets were
allocated randomly between disorders in the bivariate analyses. Exact numbers of cases and controls used in each analysis are listed in Supplementary
Tables 18.
Linear mixed model for estimation of SNP-based heritability and coheritability. We used the methods presented in Lee et al.18,35. Briefly, we estimated
the variance in case-control status explained by all SNPs using a linear
mixed model
y = Xb + g + e
Disorder risk for the study-based population (disorder risk, K). Estimates
2
of hSNP
and SNP-based coheritability from the linear model are on the casecontrol scale and so depend partly on the proportion of cases and controls
in the sample. Transformation to the liability scale allowed benchmarking of
2
hSNP
to estimates of heritability from family studies, and the transformation
accounts for the proportion of cases in the sample and depends on the assumed
disorder risk (K). The appropriate choice of K depends on the definitions of
both the phenotype (including ascertainment strategy) and the population,
which might differ between cohorts. We considered lower and upper bounds
for K in Table 1 to cover the range of possible values. rg SNP estimates are independent of scale and hence are not dependent on the choice of K.
Genome-partitioning linear mixed model. We partitioned the variance
explained by the SNPs in several ways. For example, for the univariate
linear model
y = Xb +
V(y ) = V = As g2 + Is e2
2
where s g2 is additive genetic variance tagged by the SNPs, s e is error variance,

A is the realized similarity relationship matrix estimated from SNP data19 and I
is an identity matrix. All variances were estimated on the observed case-control
scale and were transformed to the liability scale, which requires specifica2
tion of the disorder risk K to estimate hSNP
. Risk to first-degree relatives was
2
calculated from K and hSNP on the basis of the liability threshold model62.
The bivariate analyses used a bivariate extension of equation (1) (ref. 20).
The two traits were measured in different individuals, but the equations were
related through the genome-wide similarities estimated from SNPs. Genetic
and residual variances for the traits were estimated as well as the genetic
covariance g12. The genetic correlation coefficient (rg) was calculated by
(g12/(g1g2)) and is approximately the same on the observed case-control
scale as on the liability scale20 and so does not depend on specifications of K.
gt + e
t =1
with
V=
where y is a vector of case (y = 1) or control (y = 0) status (the observed scale),

is a vector for fixed effects of the overall mean (intercept), sex, sample cohort
and 20 ancestry principal components, g is the vector of random additive
genetic effects based on aggregate SNP information and e is a vector of random
error effects. X is an incidence matrix for the fixed effects relating these effects
to individuals. The variance structure of phenotypic observations is
doi:10.1038/ng.2711
The covariance g12 can be transformed to the liability scale, accounting for
assumed disorder risks and proportions of cases and controls in the samples of each disorder20, and it equals the coheritability52 rgh1h2. We used the
approximated 2 test statistic (estimate/s.e.)2 to test whether estimates were
significantly different from zero. We checked that this simple approximation
agreed well with the more formal and computer-intensive likelihood ratio
test for several examples. Heterogeneity of SNP-based heritabilities was tested
using Cochrans Q (ref. 63) and Higgins I2 (ref. 64) values, acknowledging
potential non-independence of the six estimates (three subsets plus three
subset pairs).
Ats g2t
t =1
+ Is e2
where n is the number of subsets from any non-overlapping partitioning of

SNPs; n = 22 for the joint analysis by chromosome, n = 5 for the analysis
by MAF bin and n = 3 for the analysis of SNP by gene annotation in which
SNPs were classed as CNS+ genes (2,725 genes representing 547 Mb), SNPs
in other genes (14,804 genes representing 1,069 Mb) and the remaining SNPs
not in genes. Gene boundaries were set at 50 kb from the 5 and 3 UTRs
of each gene, and CNS+ genes were the four sets identified by Raychaudhuri
et al.34 (one set comprised genes expressed preferentially in the brain compared to other tissues, and the other three sets comprised genes annotated to
be involved in neuronal activity, learning and synapses). The CNS+ set was
found to explain more of the SNP-based heritability than expected by chance
for schizophrenia35. All methods have been implemented into the freely available GCTA software65.
62. Reich, T., James, J.W. & Morris, C.A. The use of multiple thresholds in determining the
mode of transmission of semi-continuous traits. Ann. Hum. Genet. 36, 163184 (1972).
63. Cochran, W.G. The combination of estimates from different experiments. Biometrics
10, 101129 (1954).
64. Higgins, J.P., Thompson, S.G., Deeks, J.J. & Altman, D.G. Measuring inconsistency
in meta-analyses. Br. Med. J. 327, 557560 (2003).
65. Yang, J., Lee, S.H., Goddard, M.E. & Visscher, P.M. GCTA: a tool for Genome-wide
Complex Trait Analysis. Am. J. Hum. Genet. 88, 7682 (2011).
Nature Genetics

Genetic Relationship Between Five Psychiatric Disorders Estimated From Genome-Wide SNPs

Загружено:

Сведения о документе

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Genetic Relationship Between Five Psychiatric Disorders Estimated From Genome-Wide SNPs

Загружено:

Авторское право:

Доступные форматы

a n a ly s i s

Genetic relationship between five psychiatric disorders

2013 Nature America, Inc. All rights reserved.

Cross-Disorder Group of the Psychiatric Genomics Consortium*

Received 10 February; accepted 28 June; published online 11 August 2013;

VOLUME 45 | NUMBER 9 | SEPTEMBER 2013 Nature Genetics

2013 Nature America, Inc. All rights reserved.

moderate between schizophrenia and major depressive disorder at

Major depressive disorder

Disorder risk for the study-based population (disorder risk, K)b

Lower bound for disorder risk (K)

Upper bound for disorder risk (K)

Heritability estimated from twin/family studies61

Nature Genetics VOLUME 45 | NUMBER 9 | SEPTEMBER 2013

Genomic partitioning of SNP heritabilities and coheritabilities

proportions of the variance25, expressed as Nagelkerkes R2 (maximum

2013 Nature America, Inc. All rights reserved.

Figure 1 Evidence for genome-wide pleiotropy between psychiatric

Figure 2 Genomic partitioning of SNP-based heritability and SNP-based

VOLUME 45 | NUMBER 9 | SEPTEMBER 2013 Nature Genetics

2013 Nature America, Inc. All rights reserved.

use of the same assessment protocols) and genetically (for example,

SNP-based heritability or coheritability

Figure 3 SNP-based heritabilities and

would also result in nonzero estimates of SNP-based heritability from

2013 Nature America, Inc. All rights reserved.

depressive disorder is also unlikely to reflect misdiagnosis because

2013 Nature America, Inc. All rights reserved.

Nature Genetics VOLUME 45 | NUMBER 9 | SEPTEMBER 2013

2013 Nature America, Inc. All rights reserved.

Reprints and permissions information is available online at http://www.nature.com/

VOLUME 45 | NUMBER 9 | SEPTEMBER 2013 Nature Genetics

2013 Nature America, Inc. All rights reserved.

Nature Genetics VOLUME 45 | NUMBER 9 | SEPTEMBER 2013

2013 Nature America, Inc. All rights reserved.

VOLUME 45 | NUMBER 9 | SEPTEMBER 2013 Nature Genetics

2013 Nature America, Inc. All rights reserved.

Nature Genetics VOLUME 45 | NUMBER 9 | SEPTEMBER 2013

2013 Nature America, Inc. All rights reserved.

VOLUME 45 | NUMBER 9 | SEPTEMBER 2013 Nature Genetics

2013 Nature America, Inc. All rights reserved.

where s g2 is additive genetic variance tagged by the SNPs, s e is error variance,

where y is a vector of case (y = 1) or control (y = 0) status (the observed scale),

where n is the number of subsets from any non-overlapping partitioning of

Вам также может понравиться